A series of potent, selective 5HT2B receptor antagonists has been identified based upon yohimbine, with SAR studies resulting in a 1000-fold increase in 5HT2B receptor affinity relative to the starting structure (-log KBS > 10.0 have been obtained). These high-affinity tetrahydro-beta-carboline antagonists are able to discriminate among the 5HT2 family of serotonin receptors, with members of the series showing selectivities of more than 100-fold versus both the 5HT2A and 5HT2C receptors based upon radioligand binding and functional assays. As the first compounds reported with such selectivity and enhanced receptor affinity, these tetrahydro-beta-carboline antagonists are useful tools for elucidating the role of serotonin acting at the 5HT2B receptor in normal and disease physiology.
Indazoles as Indole Bioisosteres: Synthesis and Evaluation of the Tropanyl Ester and Amide of IndazoIe-3-carboxylate as Antagonists at the Serotonin 5HT3 Receptor
Three series of 6-methylergoline-8-carboxylic acid esters with various alkyl substituents in the N1-position were prepared and their 5HT2 receptor affinities measured. Some overlap occurred in the 5HT2 receptor affinities of the different ester series, indicating that both the ester side chain and the indole substituent influenced 5HT2 receptor affinity. While 5HT2 receptor affinity was affected by the structure of the ester side chain, the N1-substituent played a more crucial role in determining 5HT2 receptor affinity. When the ester side chain was held constant, maximal 5HT2 receptor affinity for that series of esters was obtained when the N1-substituent was isopropyl. Smaller substituents in the N1-position resulted in reduced 5HT2 receptor affinity. Groups C4 or larger in the N1-position resulted in a further decline in 5HT2 receptor affinity. The importance of the N1-substituent in determining 5HT2 receptor affinity was further substantiated when several 2-methyl-3-ethyl-5-(dimethylamino)indoles with various N1-substituents were tested. Again, maximal 5HT2 receptor affinity was obtained when the N1-substituent was isopropyl.
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